Synthesis and evaluation of 5-halo 2',3'-didehydro-2',3'-dideoxynucleosides and their blocked phosphoramidates as potential anti-human immunodeficiency virus agents: an example of 'kinase bypass'

A series of 5-halo derivatives of the anti-human immunodeficiency virus (HIV) nucleoside analogue d4T have been prepared by a general and highly stereoselective route. A key step is the electrophilic addition of N-iodosuccinimide to furanoid glycals. The 2'-iodo nucleosides thus obtained produced the corresponding 2',3'-didehydro-2',3'-dideoxynucleoside in a two-step elimination reaction upon treatment with potassium t-butoxide followed by sodium methoxide. The derivatives were rested for their ability to inhibit the replication of HIV-1 and HIV-2 in cell culture. Replacement of the thymine 5-methyl group of the parent nucleoside analogue (d4T) by I, CI or F resulted in compounds that showed poor antiviral activity. In view of this, we studied the application of blocked phosphate (phosphoramidate) technology to probe the efficacy of intracellular monophosphate delivery in these systems. In one case, significant antiviral potency was obtained in this way.